Busulfan-fludarabine- or treosulfan-fludarabine-based myeloablative conditioning for children with thalassemia major.

Significant advances in supportive care for patients with transfusion-dependent thalassemia major (TDT) have improved patients' life expectancy. However, transfusion-associated iron overload remains a significant barrier to long-term survival with good quality of life. Today, allogeneic hematopoietic stem cell transplantation (HSCT) is the current curative standard of care. Alongside selection of the best available donor, an optimized conditioning regimen is crucial to maximize outcomes for patients with TDT undergoing HSCT. The aim of this retrospective analysis was to investigate the role of busulfan-fludarabine-based and treosulfan-fludarabine-based conditioning in TDT patients undergoing HSCT. We included 772 patients registered in the European Society for Blood and Marrow Transplantation (EBMT) database who underwent first HSCT between 2010 and 2018. Four hundred ten patients received busulfan-fludarabine-based conditioning (median age 8.6 years) and 362 patients received treosulfan-fludarabine-based conditioning (median age 5.7 years). Patient outcomes were retrospectively compared by conditioning regimen. Two-year overall survival was 92.7% (95% confidence interval: 89.3-95.1%) after busulfan-fludarabine-based conditioning and 94.7% (95% confidence interval: 91.7-96.6%) after treosulfan-fludarabine-based conditioning. There was a very low incidence of second HSCT overall. The main causes of death were infections, graft-versus-host disease, and rejection. In conclusion, use of busulfan or treosulfan as the backbone of myeloablative conditioning for patients with TDT undergoing HSCT resulted in comparably high cure rates. Long-term follow-up studies are warranted to address the important issues of organ toxicities and gonadal function.

Lüftinger R ，Zubarovskaya N ，Galimard JE ，Cseh A ，Salzer E ，Locatelli F ，Algeri M ，Yesilipek A ，de la Fuente J ，Isgrò A ，Alseraihy A ，Angelucci E ，Smiers FJ ，La La Nasa G ，Zecca M ，Fisgin T ，Unal E ，Kleinschmidt K ，Peters C ，Lankester A ，Corbacioglu S ，EBMT Pediatric Diseases, Inborn Errors Working Parties ... -  《-》

Treosulfan-thiotepa-fludarabine-based conditioning regimen for allogeneic transplantation in patients with thalassemia major: a single-center experience from north India.

Hematopoietic stem cell transplantation (HSCT) is the definite treatment for patients with thalassemia major. A busulfan (Bu) and cyclophosphamide (Cy)-based regimen has been the standard myeloablative chemotherapy, but it is associated with higher treatment-related toxicity, particularly in patients classified as high risk by the Pesaro criteria. Treosulfan-based conditioning regimens have been found to be equally effective and less toxic. Consequently, we analyzed the safety and efficacy of treosulfan/thiotepa/fludarabine (treo/thio/flu)-based conditioning regimens for allogeneic HSCT in patients with thalassemia major between February 2010 and September 2012. We compared those results retrospectively with results in patients who underwent previous HSCT with a Bu/Cy/antithymocyte globulin (ATG)-based conditioning regimen. A treo/thio/flu-based conditioning regimen was used in 28 consecutive patients with thalassemia major. The median patient age was 9.7 years (range, 2-18 years), and the mean CD34(+) stem cell dose was 6.18 × 10(6)/kg. Neutrophil and platelet engraftment occurred at a median of 15 days (range, 12-23 days) and 21 days (range, 14-34 days), respectively. Three patients developed veno-occlusive disease, 4 patients developed acute graft-versus-host disease (GVHD), and 2 patients had chronic GVHD. Treatment-related mortality (TRM) was 21.4%. Two patients experienced secondary graft rejection. We compared these results with results in patients who underwent previous HSCT using a Bu/Cy/ATG-based conditioning regimen. Twelve patients were treated with this protocol, at a median age of 7.2 years (range, 2-11 years). One patient had moderate veno-occlusive disease, 2 patients developed acute GVHD, 2 patients had chronic GVHD, and 2 patients experienced graft rejection. There was no TRM in this group. We found no significant differences between the 2 groups (treo/thio/flu vs Bu/Cy/ATG) in terms of the incidence of acute GVHD, chronic GVHD, TRM, and graft failure, although a trend toward higher TRM was seen with the treo/thio/flu regimen.

Choudhary D ，Sharma SK ，Gupta N ，Kharya G ，Pavecha P ，Handoo A ，Setia R ，Katewa S ... -  《-》

Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3

Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. medac GmbH.

Beelen DW ，Trenschel R ，Stelljes M ，Groth C ，Masszi T ，Reményi P ，Wagner-Drouet EM ，Hauptrock B ，Dreger P ，Luft T ，Bethge W ，Vogel W ，Ciceri F ，Peccatori J ，Stölzel F ，Schetelig J ，Junghanß C ，Grosse-Thie C ，Michallet M ，Labussiere-Wallet H ，Schaefer-Eckart K ，Dressler S ，Grigoleit GU ，Mielke S ，Scheid C ，Holtick U ，Patriarca F ，Medeot M ，Rambaldi A ，Micò MC ，Niederwieser D ，Franke GN ，Hilgendorf I ，Winkelmann NR ，Russo D ，Socié G ，Peffault de Latour R ，Holler E ，Wolff D ，Glass B ，Casper J ，Wulf G ，Menzel H ，Basara N ，Bieniaszewska M ，Stuhler G ，Verbeek M ，Grass S ，Iori AP ，Finke J ，Benedetti F ，Pichlmeier U ，Hemmelmann C ，Tribanek M ，Klein A ，Mylius HA ，Baumgart J ，Dzierzak-Mietla M ，Markiewicz M ... -  《Lancet Haematology》

European Society for Blood and Marrow Transplantation Analysis of Treosulfan Conditioning Before Hematopoietic Stem Cell Transplantation in Children and Adolescents With Hematological Malignancies.

Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n = 71, AML n = 47, MDS/MPS n = 40, other leukemia/lymphoma n = 25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45 ± 4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P = 0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P = 0.048) and a trend toward better EFS. Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation.

Boztug H ，Sykora KW ，Slatter M ，Zecca M ，Veys P ，Lankester A ，Cant A ，Skinner R ，Wachowiak J ，Glogova E ，Pötschger U ，Peters C ... -  《-》

Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile. To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468). At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease. Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society.

Nagler A ，Labopin M ，Beelen D ，Ciceri F ，Volin L ，Shimoni A ，Foá R ，Milpied N ，Peccatori J ，Polge E ，Mailhol A ，Mohty M ，Savani BN ... -  《-》